Asymmetric Total Syntheses of Colchicine, β-Lumicolchicine, and

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Asymmetric Total Syntheses of Colchicine, β‑Lumicolchicine, and Allocolchicinoid N‑Acetylcolchinol‑O‑methyl Ether (NCME) Xin Liu,†,‡,∥ Ya-Jian Hu,†,‡,∥ Bo Chen,‡,∥ Long Min,‡ Xiao-Shui Peng,§ Jing Zhao,*,† Shaoping Li,*,† Henry N. C. Wong,§ and Chuang-Chuang Li*,‡ †

Institute of Chinese Medical Sciences, University of Macau, Macao, China Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China § Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China ‡

S Supporting Information *

ABSTRACT: A concise and highly enantioselective synthesis of colchicine (>99% ee) in eight steps and 9.3% overall yield, without the need for protecting groups, was developed. A unique Wacker oxidation was used for enabling regioselective construction of the highly oxidized and synthetic challenging tropolone C-ring. Furthermore, asymmetric syntheses of βlumicolchicine and N-acetylcolchinol-O-methyl ether (NCME) were achieved. Notably, NCME was synthesized from βlumicolchicine by an unusual decarbonylation and electrocyclic ring-opening cascade reaction.

olchicine (1), which is an alkaloid natural product, was the first tubulin-destabilizing agent to be reported in the literature (Figure 1).1 This material has also been investigated against a variety of different indications because of its remarkable antimitotic activity. Furthermore, in a similar manner to many other tubulin-binding natural products (e.g., taxol and the epothilones), colchicine has been used to treat several diseases, including acute gout and familial Mediterra-

C

nean fever.1 Colchicine has also been used as a neurotoxin in animal models of Alzheimer’s disease and epilepsy,2 as well as to treat chronic myelocytic leukemia. However, its high toxicity has precluded its clinical use in cancer chemotherapy.3 Interestingly, some of the allocolchicines including Nacetylcolchinol-O-methyl ether (NCME) (2), which are biphenyl analogues of colchicine, have been found to be active against various cancer cell lines, including drug-resistant ones. They operate by inhibiting tubulin assembly and polymerization, leading to the arrest of cell mitosis.4 Structurally, colchicine (1) possesses an unusual 6−7−7 tricyclic ring system, and NCME (2) possesses a 6−7−6 carbocyclic skeleton. The stereocenter at C-7 and the aRconfigured chiral axis defined by the pivot bond joining the A and C rings, and the regioselective construction of the highly oxidized tropolone C-ring, represent formidable synthetic challenges.5 It is noteworthy that another colchicinoid βlumicolchicine (3) has a novel tetracyclic 6−7−4−5 membered ring system with three stereocenters, and α-lumicolchicine (4) has a unique nonacyclic 6−7−4−5−4−5−4−7−6 ring skeleton with ten stereocenters.6 Owing to their unusual structural motifs and promising pharmacological properties, colchicine (1) and NCME (2) have attracted considerable attention from synthetic chemists, which has resulted in several elegant total syntheses of 17,8 and

Figure 1. Structures of colchicine, NCME, and β-lumicolchicine.

Received: July 20, 2017 Published: August 19, 2017

© 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b02224 Org. Lett. 2017, 19, 4612−4615

Letter

Organic Letters 2.9 Recently, we developed an enantioselective synthesis of colchicine (1) from commercially available and inexpensive 2,3,4-trimethoxybenzaldehyde (5).7e The challenging tricyclic 6−7−7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction.10 In our continuing efforts toward the synthesis of biologically active natural products,11 we herein describe a modified concise and highly enantioselective synthesis of colchicine using the Wacker oxidation for the regioselective construction of the highly oxidized tropolone C-ring. Moreover, asymmetric total syntheses of β-lumicolchicine and NCME were also achieved. Retrosynthetically (Figure 2), β-lumicolchicine (3) could be prepared from colchicine (1) through a 4π-electrocyclization

Compound 7 could be synthesized from 5 through several simple functional group transformations reported previously.7e Our synthesis began with the preparation of 6 (>99% ee) from 5 in 5 steps in 21.8% overall yield, as reported previously (Scheme 1).7e The diastereoselective reduction of the ketone Scheme 1. Asymmetric Total Synthesis of 1

group in 6, followed by the in situ chemoselective methylation of the resulting alcohol, afforded 8 in 75% yield (1.0 g scale). The structure of 8 was unambiguously confirmed using X-ray crystallography. After extensive experimentation, we found that the regioselective Wacker oxidation of the substituted olefin using air as a co-oxidant gave ketone 9 in good yield. We reasoned that the methoxy group at C10 in 8 was critical for this regioselective outcome. Finally, the double elimination of the oxa-bridge in 9 proceeded smoothly using a slightly modified version of Cha’s procedure7c in the presence of TMSOTf and Me2EtN in DCM to complete our total synthesis of (−)-1 in 81% yield in >99% ee. The 1H and 13C NMR spectra of synthetic 1, as well as its optical rotation, were identical to those of the natural product. With colchicine (1) in hand, we proceeded to investigate our proposed syntheses of β-lumicolchicine (3) and NCME (2) (Scheme 2). The irradiation of a 10:1 (v/v) CH3CN/acetone solution of 1 (0.0025 mol/L) with a 125 W high-pressure mercury arc lamp surrounded by a Pyrex water jacket for 25 min resulted in β-lumicolchicine (3) with a much improved yield6 of 68%. Subsequently, the proposed transition-metal-catalyzed decarbonylation/electrocyclic ring-opening cascade reaction of 3 was attempted using several different catalysts (Rh, Ni, and Pd) in a variety of different solvents, as reported previously.12 However, these conditions failed to afford any of the desired product of 2. To our delight, the irradiation of a solution of β-

Figure 2. Retrosynthetic analysis of 1−3.

reaction.6 We anticipate that NCME (2) would be synthesized from 3 through a Rh-catalyzed decarbonylation process12 via intermediate A to give the fused bicyclobutene B, followed by an electrocyclic ring-opening reaction.13 The formation of the more stable aromatic ring C is one of the driving forces for this process. It was envisioned that colchicine (1) could be generated from 6 through a Wacker oxidation,14 followed by the regioselective formation of the tropolone C-ring. Tricyclic 6 could itself be synthesized from 7 through the intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. 4613

DOI: 10.1021/acs.orglett.7b02224 Org. Lett. 2017, 19, 4612−4615

Organic Letters

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Scheme 2. Asymmetric Synthesis of 2 and 3

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02224. Detailed experimental procedure, and 1H NMR and 13C NMR spectra, as well as X-ray data information (PDF) Crystallographic data (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Chuang-Chuang Li: 0000-0003-4344-0498 Author Contributions ∥

X.L., Y.-J.H., and B.C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of China (Grant Nos. 21402083, 21502087, 21522204, 21472081, and 21672095), Guangdong Science and Technology Department (2016A050503011), the Shenzhen Science and Technology Innovation Committee (Grant Nos. JCYJ20170412152454807, JSGG20160301103446375, and KQTD2015071710315717), and Innovation and Technology Fund (GHP/ 004/16GD) from Innovation and Technology Commission, HKSAR.

lumicolchicine (3) in 10:1 (v/v) CH3CN/acetone (0.0024 mol/L) with a 125 W high-pressure mercury arc lamp surrounded by a Pyrex water jacket for 20 min gave 2 in 54% yield instead of α-lumicolchicine (4)6 and colchicine. The outcome of this transformation suggested that under the irradiation compound 3 had probably undergone a decarbonylation process to generate the intermediate B, followed by the anticipated retro-4π-electrocyclization reaction to give 2, which has been reported to exhibit greater inhibitory activity toward tubulin than colchicine.4d The 1H and 13C NMR spectra of synthetic 2 and 3, as well as their optical rotation, were identical to those of the natural products. We also have tried to extend the time of irradiation for one-pot synthesis of compound 2 from 1, but a trace of 2 was detected. Probably, other unidentified compounds made the reaction more complex, with the time extended and the temperature of the solution increased. So, after many attempts, we found that 25 min is the best time length for the first irradiation and the two-step sequence is more efficient than the one-pot procedure for the preparation of 2 from 1. In summary, we developed a concise and highly enantioselective synthesis of colchicine (>99% ee) in eight steps in 9.3% overall yield without the need for protecting groups.15 An unusual Wacker oxidation was used for enabling the regioselective construction of the highly oxidized tropolone C-ring. β-Lumicolchicine was prepared through a 4π-electrocyclization reaction with a much-improved yield compared with existing procedures, and the allocolchicinoid NCME was synthesized from β-lumicolchicine through a novel decarbonylation/electrocyclic ring-opening cascade reaction.

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REFERENCES

(1) (a) Boye, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell, G. A., Eds.; Academic Press: San Diego, 1992; Vol. 41, p 125. (b) Le Hello, C. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 2000; Vol. 53, p 287. (c) Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Med. Res. Rev. 2008, 28, 155. (d) Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253. (e) Ravelli, R. B. G.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Nature 2004, 428, 198. (2) Weiner, J. L.; Buhler, A. V.; Whatley, V. J.; Harris, R. A.; Dunwiddie, T. V. J. Pharmacol. Exp. Ther. 1998, 284, 95. (3) Finkelstein, Y.; Aks, S. E.; Hutson, J. R.; Juurlink, D. N.; Nguyen, P.; Dubnov-Raz, G.; Pollak, U.; Koren, G.; Bentur, Y. Clin. Toxicol. 2010, 48, 407. (4) (a) Perez-Ramirez, B.; Gorbunoff, M. J.; Timasheff, S. N. Biochemistry 1998, 37, 1646. (b) Guan, J.; Zhu, X.; Brossi, A.; Tachibana, Y.; Bastow, K. F.; Verdier-Pinard, P.; Hamel, E.; McPhail, A. T.; Lee, K. Collect. Czech. Chem. Commun. 1999, 64, 217. (c) Büttner, F.; Bergemann, S.; Guénard, D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg. Med. Chem. 2005, 13, 3497. (d) Nakagawa-Goto, K.; Jung, M. K.; Hamel, E.; Wu, C.-C.; Bastow, K. F.; Brossi, A.; Ohta, S.; Lee, K.-H. Heterocycles 2005, 65, 541. (5) (a) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43, 3230. (b) Liu, N.; Song, W.; Schienebeck, C. M.; Zhang, M.; Tang, W. Tetrahedron 2014, 70, 9281. (6) (a) Grewe, R.; Wulf, W. Chem. Ber. 1951, 84, 621. (b) Chapman, O. L.; Smith, H. G. J. Am. Chem. Soc. 1961, 83, 3914. (c) Chapman, O. L.; Smith, H. G.; King, R. W. J. Am. Chem. Soc. 1963, 85, 803. For the references above, different from our conditions, irradiation of 4614

DOI: 10.1021/acs.orglett.7b02224 Org. Lett. 2017, 19, 4612−4615

Letter

Organic Letters colchicine utilized sunlight in H2O solution for 2 months to give α,β,γlumicolchicines together. (7) (a) Schreiber, J.; Leimgruber, W.; Pesaro, M.; Schudel, P.; Eschenmoser, A. Angew. Chem. 1959, 71, 637. (b) Banwell, M. G. Pure Appl. Chem. 1996, 68, 539. (c) Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org. Chem. 1998, 63, 2804. (d) Graening, T.; Bette, V.; Neudorfl, J.; Lex, J.; Schmalz, H. G. Org. Lett. 2005, 7, 4317. (e) Chen, B.; Liu, X.; Hu, Y.; Zhang, D.; Deng, L.; Lu, J.; Min, L.; Ye, W.; Li, C.-C. Chem. Sci. 2017, 8, 4961. (8) For selected synthesis, see: (a) Van Tamelen, E. E.; Spencer, T. A., Jr; Allen, D. S., Jr; Orvis, R. L. J. Am. Chem. Soc. 1959, 81, 6341. (b) Woodward, R. B. Harvey Lect. 1963, 59, 31. (c) Evans, D.; Tanis, S.; Hart, D. J. Am. Chem. Soc. 1981, 103, 5813. (d) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6713. (e) Graening, T.; Friedrichsen, W.; Lex, J.; Schmalz, H. G. Angew. Chem., Int. Ed. 2002, 41, 1524. (f) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 2293. (g) For a summary of colchicinoid synthesis, see refs 5a and 7e (Table S4 in Supporting Information) for details. (9) (a) Seganish, W. M.; DeShong, P. Org. Lett. 2006, 8, 3951. (b) Djurdjevic, S.; Green, J. R. Org. Lett. 2007, 9, 5505. For other allocolchicine syntheses, see: (c) Sawyer, J. S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29, 4839. (d) Vorogushin, A. V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68, 5826. (e) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849. (f) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (g) Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem. 2006, 4, 2193. (h) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir, J. C.; Maudet, M. Tetrahedron Lett. 2007, 48, 4627. For oxidative degradation method, see: (i) Iorio, M. A. Heterocycles 1984, 22, 2207. (j) Brecht, R.; Haenel, F.; Seitz, G. Liebigs Ann./Recl. 1997, 1997, 2275. (k) Dilger, U.; Franz, B.; Roettele, H.; Schroeder, G.; Herges, R. J. Prakt. Chem./Chem.-Ztg. 1998, 340, 468. (10) For related studies of [5 + 2] cycloaddition reaction from our group, see: (a) Mei, G.; Liu, X.; Qiao, C.; Chen, W.; Li, C.-C Angew. Chem., Int. Ed. 2015, 54, 1754. (b) Mei, G.; Yuan, H.; Gu, Y.; Chen, W.; Chung, L. W.; Li, C.-C. Angew. Chem., Int. Ed. 2014, 53, 11051. (c) Liu, X.; Liu, J.-Y.; Zhao, J.; Li, S.; Li, C.-C. Org. Lett. 2017, 19, 2742. For review and selected application of [5 + 2] cycloaddition reaction in natural product synthesis, see: (d) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244. (e) Zhang, M.; Liu, N.; Tang, W. J. Am. Chem. Soc. 2013, 135, 12434. (f) He, C.; Hu, J.; Wu, Y.; Ding, H. J. Am. Chem. Soc. 2017, 139, 6098. (11) (a) Qiao, C.; Zhang, W.; Han, J.; Li, C.-C. Org. Lett. 2016, 18, 4932. (b) Han, J. C.; Li, F.; Li, C.-C. J. Am. Chem. Soc. 2014, 136, 13610. (c) Liu, G.; Mei, G. J.; Chen, R.; Yuan, H.; Yang, Z.; Li, C.-C. Org. Lett. 2014, 16, 4380. (d) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li, C.-C. Angew. Chem., Int. Ed. 2013, 52, 620. (12) For seminal reports on the decarbonylation process of ketones using a transition metal, see: (a) Rusina, A.; Vlcek, A. A. Nature 1965, 206, 295. (b) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (c) Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 8285. For selected recent examples, see: (d) Lei, Z.-Q.; Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Sun, J.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 2690. (e) Dermenci, A.; Whittaker, R.; Dong, G. Org. Lett. 2013, 15, 2242. (f) Whittaker, R.; Dong, G. Org. Lett. 2015, 17, 5504. Theoretical study: (g) Dermenci, A.; Whittaker, R. E.; Gao, Y.; Cruz, F. A.; Yu, Z.-X.; Dong, G. Chem. Sci. 2015, 6, 3201. (h) Morioka, T.; Nishizawa, A.; Furukawa, T.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2017, 139, 1416. (i) Somerville, R. J.; Martin, R. Angew. Chem., Int. Ed. 2017, 56, 6708. (13) (a) Wingert, H.; Regitz, M. Chem. Ber. 1986, 119, 244. (b) Wingert, H.; Irngartinger, H.; Kallfass, D.; Regitz, M. Chem. Ber. 1987, 120, 825. (c) Maier, G.; Fleischer, F.; Kalinowski, H.-O. Liebigs Ann. 1995, 1995, 173. For related studies, see: (d) Dolbier, W. R.; Koroniak, H.; Burton, D. J.; Bailey, A. R.; Shaw, G. S.; Hansen, S. W. J. Am. Chem. Soc. 1984, 106, 1871. (e) Kirmse, W.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1984, 106, 7989. (f) Tallarico, J. A.; Randall, M. L.; Snapper, M. L. J. Am. Chem. Soc. 1996, 118, 9196. (g) Deak, H. L.; Williams, M. J.; Snapper, M. L. Org. Lett. 2005, 7,

5785. (h) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A. M.; Smith, M. W.; Moss, F. R.; Smith, M. D.; Vahala, R.; GonzalezMartinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016, 138, 15845. (i) Boon, B. A.; Green, A. G.; Liu, P.; Houk, K. N.; Merlic, C. A. J. Org. Chem. 2017, 82, 4613. For a review on biomimetic electrocyclization, see: (j) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005, 105, 4757. For the application of cyclobutane derivatives in organic synthesis, see: (k) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (14) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Rüttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. (b) Tsuji, J. Synthesis 1984, 1984, 369. (c) Takacs, J. M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369. (d) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the 21st Century, 2nd ed.; John Wiley & Sons, Ltd: Chichester, U.K., 2004. (e) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221. (f) Jira, R. Angew. Chem., Int. Ed. 2009, 48, 9034. (g) Sigman, M. S.; Werner, E. W. Acc. Chem. Res. 2012, 45, 874. (h) Michel, B. W.; Steffens, L. D.; Sigman, M. S. Org. React. 2014, 84, 75. (i) Mann, S. E.; Benhamou, L.; Sheppard, T. D. Synthesis 2015, 47, 3079. (j) Baiju, T. V.; Gravel, E.; Doris, E.; Namboothiri, I. N. N. Tetrahedron Lett. 2016, 57, 3993. (15) (a) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193. For selected recent syntheses using a protecting-group-free strategy, see: (c) Zhao, Y.-M.; Maimone, T. J. Angew. Chem., Int. Ed. 2015, 54, 1223. (d) Jansen, D. J.; Shenvi, R. A. J. Am. Chem. Soc. 2013, 135, 1209. (e) Ge, H. M.; Zhang, L.-D.; Tan, R. X.; Yao, Z.-J. J. Am. Chem. Soc. 2012, 134, 12323. (f) Zhou, Q.; Chen, X.; Ma, D.-W. Angew. Chem., Int. Ed. 2010, 49, 3513. (g) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (h) McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738.

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